Efficacy and safety of selective internal radiotherapy with yttrium-90 resin microspheres compared with sorafenib in locally advanced and inoperable hepatocellular carcinoma (SARAH): an open-label randomised controlled phase 3 trial

Pereira, Héléna; Dinut, Aurélia; Châtellier, Gilles; Assenat, Éric; Christol, Elisabeth Delhom -; Guiu, Boris; Ilonca, Alina Diana; Lonjon, J.; Pageaux, Georges‐Philippe; Abdel‐Rehim, Mohamed; Allaham, Wassim; Bouattour, Mohamed; Castéra, Laurent; Dieudonné, Arnaud; Lebtahi, Rachida; Ronot, Maxime; Sibert, Annie; Vilgrain, Valérie; Barraud, Hélène; Bazin, Christophe; Bronowicki, Jean–Pierre; Vallar, Laurent; Mathias, Elodie; Chagneau‐Derrode, Carine; Perdrisot, R.; Silvain, Christine; Tasu, J.P.; Borentain, Patrick; Gerolami, René; Mundler, O.; Seitz, Jean‐François; Vidal, Vincent; Aubé, Christophe; Bouvier, Antoine; Couturier, O.; Oberti, Frédéric; Brenot-Rossi, I.; Raoul, Jean‐Luc; Sarran, Anthony; Chalaye, Julia; Costentin, Charlotte; Itti, Emmanuel; Kobeiter, Hicham; Luciani, Alain; Adam, René; Lewin, M.; Samuel, Didier; Edeline, Julien; Garin, Étienne; Rolland, Yan; Archambeaud, Isabelle; Eugène, Thomas; Frampas, É.; Cassinotto, Christophe; Guyot, M.; Hiriart, Jean‐Baptiste; Lapuyade, Bruno; Vergniol, Julien; Bachellier, Philippe; Détour, Julien; Duclos, Bernard; Greget, Michel; Habersetzer, François; Impériale, Alessio; Merle, Philippe; Rode, Agnès; Morvan, J.; Nguyen‐Khac, Eric; Yzet, Thierry; Baudin, G.; Chevallier, P.; Mahamat, Abakar; Piche, Thierry; Razzouk, M.; Hillon, Patrick; Loffroy, Romaric; Toubeau, Michel; Vincent, Julie; Barabino, Gabriele; Bouarioua, Nadia; Cuilleron, Muriel; Ecochard, Marie; Prévôt-Bitot, Nathalie; Leroy, Vincent; Roux, Julie; Sengel, Christian; Bourcier, Valérie; Ganne‐Carrié, Nathalie; Séror, Olivier; Costo, Sylvie; Dao, Thông; Pelage, Jean-Pierre; Dumortier, Jérôme; Giammarile, Francesco; Valette, Pierre-Jean; Ghazzar, N.; Pellerin, Olivier; Taı̈eb, Julien; Weinmann, Pierre; Heurgué–Berlot, Alexandra; Marcus, C.; Sommacale, Danièle; Castilla-Lièvre, Maria-Angéla; Maître, Sophie; Marthey, Lysiane

doi:10.1016/s1470-2045(17)30683-6

Cited by 620 publications

(424 citation statements)

References 26 publications

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“…Our meta-analysis included more data than previous meta-analyses, in which recent published clinical trials have not been updated 12,15,16,18–20. In addition, our meta-analysis included randomized Phase III trials only.…”

Section: Discussionmentioning

confidence: 99%

“…Selective internal radiation (SIRT) might be an alternative therapy to sorafenib with less toxicity in locally advanced HCC patients 15,16. SIRT with yttrium 90 ( 90 Y) microspheres is a therapeutic procedure applied via the hepatic artery, delivering brachytherapy directly to liver tumors.…”

Section: Introductionmentioning

confidence: 99%

“…In the SARAH and SIRVENIB trials, OS and TTP in the SIRT group were similar to the sorafenib group among patients with locally advanced HCC. However, ORR and AE frequency were improved with SIRT over sorafenib 15,16…”

Section: Introductionmentioning

confidence: 99%

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Alternative treatment strategies to sorafenib in patients with advanced hepatocellular carcinoma: a meta-analysis of randomized Phase III trials

Wang

He-fang

Yü

et al. 2018

OTT

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IntroductionThis meta-analysis was conducted to evaluate efficacy and safety in patients treated with sorafenib vs other tyrosine-kinase inhibitors (TKIs) or selective internal radiotherapy (SIRT) for advanced hepatocellular carcinoma (HCC).MethodsElectronic databases were systematically reviewed for randomized Phase III trials comparing sorafenib with other TKIs or SIRT in advanced HCC. Sorafenib was defined as the control arm. Other TKIs or SIRT was defined as the experimental arm. Overall survival (OS), time to progression (TTP), objective response rate (ORR), disease-control rate (DCR), and adverse events (AEs) were reviewed. Four trials in the other-TKI group (n=4,218) and two in the SIRT group (n=819) were eligible.ResultsCompared with sorafenib, other TKIs showed similar benefit on OS (HR 1.08, 95% CI 0.93–1.24; P=0.31) and TTP (HR 0.86, 95% CI 0.66–1.12; P=0.26) for advanced HCC. A significant increase in ORR (RR 1.67, 95% CI 1.15–2.43; P=0.008) was found with other TKIs, but no increase in DCR (RR 1.11, 95% CI 0.98–1.26; P=0.11) was observed. Other TKIs were associated with more frequent grade 3/4 AEs than sorafenib, including hypertension (P<0.00001), thrombocytopenia (P=0.002), fatigue (P<0.00001), decreased appetite (P<0.00001), and vomiting (P<0.0001). For locally advanced HCC, neither OS (HR 1.14, 95% CI 0.98–1.32; P=0.09) nor TTP (HR 0.87, 95% CI 0.74–1.02; P=0.10) differed significantly in SIRT and sorafenib. There was an increase in ORR (RR 2.60, 95% CI 1.69–4.00; P<0.0001), but no improvement in DCR (RR 0.91, 95% CI 0.81–1.02; P=0.11) in the SIRT group. Fewer patients treated with SIRT had grade 3/4 AEs than those treated with sorafenib, including diarrhea (P<0.0001), fatigue (P=0.0006), and hand–foot syndrome (P=0.0002). Other TKIs were noninferior to sorafenib in OS and TTP in advanced HCC, but with increased risk of toxicities.ConclusionPatients with locally advanced HCC treated with SIRT got similar efficacy with less toxicity to those treated with sorafenib.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Alternative treatment strategies to sorafenib in patients with advanced hepatocellular carcinoma: a meta-analysis of randomized Phase III trials

Wang

He-fang

Yü

et al. 2018

OTT

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“…A superiority trial of sorafenib plus erlotinib (SEARCH trial) [7], a superiority trial of sorafenib plus doxorubicin (CALGB808028 trial), and a trial investigating sorafenib plus hepatic arterial infusion chemotherapy (HAIC) (SILIUS trial) [8] all failed. The results of two superiority trials comparing sorafenib with radioembolization called SARAH (SorAfenib versus Radioembolization in Advanced Hepatocellular carcinoma) [9] and SIRveNIB (Study to Compare Selective Internal Radiation Therapy [SIRT] Versus Sorafenib in Locally Advanced Hepatocellular Carcinoma [HCC]) were also reported at EASL 2017 and ASCO 2017, although these trials failed as well [10]. These results highlight the diffi- culties associated with conducting clinical trials of first-line HCC drugs using OS as the endpoint, and demonstrate the superiority of sorafenib for improving survival compared with other drugs.…”

Section: Introductionmentioning

confidence: 99%

Lenvatinib May Drastically Change the Treatment Landscape of Hepatocellular Carcinoma

Kudo

2018

Liver Cancer

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“…The analysis of the data available on large registries [13,32,56,59,62,72] could represent the basis to identify prognostic factors enabling patients' stratification in the different stages. Indeed, the failure of some of the largest recent randomized studies [78,79] demonstrates that there cannot be scientific development when trials are conducted in a generalized, unselected population. Thus, these subclassifications should represent the next step to build the basis for future research and randomized controlled trials involving intermediate-to advanced-stage HCC patients.…”

mentioning

confidence: 99%

Patients with Barcelona Clinic Liver Cancer Stages B and C Hepatocellular Carcinoma: Time for a Subclassification

Golfieri

Bargellini²,

Spreafico

et al. 2018

Liver Cancer

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Background: The Barcelona Clinic Liver Cancer (BCLC) intermediate and advanced stages (BCLC B and C) of hepatocellular carcinoma (HCC) both include heterogeneous populations. Patients classified as BCLC stage B present with different tumour burdens, and the recommended treatment is transarterial chemoembolization (TACE). A similar heterogeneity of tumour burden and liver function can be found among patients classified as BCLC stage C, which includes diverse clinical features (performance status [PS] 1–2), macrovascular invasion (MVI) including portal vein tumour (PVT) thrombosis, and/or extra-hepatic spread. Nonetheless, the anti-tumoural treatment formally recommended by Western guidelines is systemic therapy with sorafenib. Summary: Several proposals of subclassification for both these stages have been suggested in recent years, differentiating the more appropriate treatments for each substage. In particular, for BCLC stage C patients with PVT, therapeutic indications, clinical outcomes, and response to locoregional therapy are notably different in the presence of subsegmental, segmental or main PVT. Accordingly, liver resection and transarterial therapies, such as TACE or transarterial embolization (TAE) and ⁹⁰Y-radioembolization (TARE), can be performed in locally advanced HCC with intrahepatic MVI according to its extent. In fact, surgery and TACE/TAE/TARE have no contraindications in the presence of PVT limited to the subsegmental or segmental branches in Child-Pugh class A patients, whereas only TARE should be utilized when there is lobar branch involvement. The presence of PS 1 should not be sufficient to allocate patients to the advanced stage since this would preclude any potential treatment for HCC. Patients should be properly classified as BCLC C only in cases of main portal trunk PVT, and treated according to the guidelines, provided that they belong to Child-Pugh class A. Key Messages: Subclassifications of BCLC B and C stages are urgently needed and require validation in order to guide clinicians towards the most effective treatment option.

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Efficacy and safety of selective internal radiotherapy with yttrium-90 resin microspheres compared with sorafenib in locally advanced and inoperable hepatocellular carcinoma (SARAH): an open-label randomised controlled phase 3 trial

Cited by 620 publications

References 26 publications

Alternative treatment strategies to sorafenib in patients with advanced hepatocellular carcinoma: a meta-analysis of randomized Phase III trials

Alternative treatment strategies to sorafenib in patients with advanced hepatocellular carcinoma: a meta-analysis of randomized Phase III trials

Lenvatinib May Drastically Change the Treatment Landscape of Hepatocellular Carcinoma

Patients with Barcelona Clinic Liver Cancer Stages B and C Hepatocellular Carcinoma: Time for a Subclassification

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